1. Field of the Invention
Retinol (vitamin A) and retinoic acid (vitamin A acid), its isomers, and certain of its analogs are known to have beneficial effects in the treatment of acne and keratinizing skin disorders.
Acne affects large patient populations and is a common inflammatory skin disorder which usually localizes on the face. Fortunately, the disease usually disappears and in the interval of months or years between onset and resolution, therapy, although not curative, can satisfactorily suppress the disease in the majority of patients.
A small number of acne patients with severe disease show little or no response to intensive therapeutic efforts including the use of high doses of oral tetracyline, dapsone, prednisone and, in women, estrogen. In many cases, these drugs afford only a modest degree of control while the side effects of these agents severely restrict their usefulness. Patients with nodulocystic acne suffer from large, inflammatory, suppurative nodules appearing on the face, and frequently the back and chest. In addition to their appearance, the lesions are tender and often purulently exudative and hemorrhagic. Disfiguring scars are frequently inevitable.
Therapies for acne involves local and systemic administration of vitamin compounds, collectively known as retinoids. Topical application of all-trans-retinoic acid has been tried with some success, particularly against comedones or blackheads, but this condition frequently returns when the treatment is withdrawn. (All-trans-retinoic acid is also known as tretinoin. These terms are used interchangeably throughout this specification.) Additionally, retinoic acid applied topically can be highly irritating and its use can be painful for the patient depending on the concentration used and the frequency of application.
A number of side effects complicates the administration of large doses of vitamin A. Among the many symptoms of hypervitaminosis A are weight loss, desquamation of the skin, hair loss, irritation of the oral and pharyngeal mucosa, and nose bleeds, headaches, bone pain, liver toxicity due to storage of vitamin A in the liver, papilledena, pseudotumor cerebri, demineralization and periosteal thickening of bones. Because of these and other side effects of oral treatment with vitamin A and all-trans-retinoic acid, which produces similar side effects, is rarely recommended for dermatopathic conditions.
The present invention relates to 13-cis-retinoic acid esters which are effective in the treatment of acne and other skin disorders when administered either topically and which show few if any side effects.
2. Description of the Prior Art
The successful use of 13-cis-retinoic acid, administered orally, for the treatment of cystic and conglobate acne was reported in Peck, et al., "Prolonged Remissions of Cystic and Conglobate Acne with 13-cis-Retinoic Acid," New Eng. J. Med. 300: 329-333 and 30: 359-360, Feb. 15, 1979. (13-cis-retinoic acid is also known as isotretinoin. These terms are used interchangeably throughout this specification.) In this study, a four month course of therapy with oral 13-cis-retinoic acid was begun at a minimum divided dosage of 1.0 mg per kilogram of body weight per day. The dosage was then increased in increments of 0.5 to 1.0 mg/kg/day at intervals of two to four weeks until either an appreciable therapeutic effect or dose-limiting toxicity was observed.
A report of the above study is also found in Gunby, "Synthetic Retinoid Used in Dermatopathies," J.A.M.A. 240: 610, Aug. 18, 1978. In this report, it is further stated that the oral dosages used were from 80 to 240 mg/day of 13-cis-retinoic acid in capsule form with an average dose of 140 mg/day. Still another report of this study will be found in Peck, et al., "Treatment of Darier's Disease, Lamellar Ichthyosis, Pityriasis Rubra Pilaris, Cystic Acne and Basal Cell Carcinoma with Oral 13-cis-Retinoic Acid," Dermat. 157 (Supp. 1): 11-12 (1978).
Belgian Patent No. 762,344 of Aug. 2, 1971, also discloses the use of orally administered 13-cis-retinoic acid for the treatment of acne (unspecified) and psoriasis. However, only a general dosage for various vitamin A compounds of from 0.1 mg to 0.5 mg to about 3.0 mg per kilogram of body weight is disclosed. Moreover, there is no example directed towards the use of 13-cis-retinoic acid.
In "Investigational Drug Brochure R04-3780," printed by Hoffman-LaRoche Inc., there appear several general statements indicating that all-trans-retinoic acid had been used for oral treatment of acne, and that 13-cis-retinoic acid had been proved to be less toxic than all-trans retinoic acid in animal experiments. There is also the statement that: "Skin diseases characterized by accelerated or pathological keratinization may respond to treatment with R04-3780 (sic: 13-cis-retinoic acid), . . . as well as acne." However, dosages were not discussed.
In a later edition of "Investigational Drug Brochure R04-3780", Feb. 1978, It is disclosed that interest in the therapeutic applications of 13-cis-retinoic acid developed when preliminary testing indicated that it had epithelium-protecting ability equivalent to retinoic acid and was apparently less toxic. There is a further disclosure of the treatment of an unspecified acne with 13-cis-retinoic acid administered orally, but with no indication of the method of varying dosage which is the subject of this invention.
The "Handbook of Nonprescription Drugs," 5th ed., 1977, A.P.A. pub., Pp 140, 319, 320, discloses the use of vitamin A and retinoic acid, but not the 13-cis-stereoisomer, in the treatment of acne (unspecified). However, the disclosure of this publication is opposite to that of the subject invention, in that it states: "The systemic use of vitamin A for the treatment of acne, . . . is not warranted by clinical evidence." at page 140; and that: "Treatments that have been abandoned or have not been proved effective include oral vitamin A, . . ." at page 320.
J. V. Straumford reported a systemic usage of large oral doses of retinol, the alcohol form of vitamin A, over a long period of time for the treatment of acne (Straumford, J. V., "Vitamin A: Its Effect on Acne," Northwest Med., 42: 219-255, August, 1943). These results, however, have been disputed and systemic therapy of acne utilizing retinol has been challenged by other investigators (Anderson, J. A. D., et al., "Vitamin A in Acne Vulgaries," Brit. Med. J., 2: 294-296, August, 1963; Lynch, F. W., et al., "Acne Vulgaris Treated with Vitamin A," Arch. Derm. 55: 355, 357, March 1947; and Mitchell, G. H., et al., "Results of Treatment of Acne Vulgaris by Intramuscular Injections of Vitamin A," Arch. Derm. 64: 428-434, October, 1951).
Topical administration of retinoic acid for the treatment of acne was reported by Kligman, et al., (Arch. Derm. 99: 469-476, 1969, U.S. Pat. No. 3,729,568). The effectiveness of this treatment as disclosed by Kligman is often associated with a noticeable irritating effect of topically applied retinoic acid.
Esters and amides of trans-retinoic acid which are useful for the treatment of acne are claimed in U.S. Pat. Nos. 4,055,659 (all trans-retinoyloxyacetamide) 4,126,697 (4-(all-trans-rentinoyloxyacetyl)-catechol), 4,126,698 (2-hydroxyethyl all-trans-retinoate) and 4,304,787 (benzyl all-trans-retinoate). All four of these patents to Gander, et al. also disclose mixed 2-hydroxy-1-propyl and 1-hydroxy-2-propyl all-trans-retinoates, N-(3,4-methylenedioxyphenylmethyl) all-trans-retinamide, and 4-nitrobenzyl all-trans-retinoate. The effectiveness of all these compounds was shown through testing which measured increase in DNA synthesis in epidermal cells. This ability has been associated with the effectiveness of retinoic acid in the treatment of acne. See, for example, Christophers and Braun-Falco, "Stimulation of Epidermal DNA-Synthesis with Vitamin A-Acid," Arch. Klin. exp. Derm. 232: 427-433 (1968) and Wolfe, et al., "Changes in Epidermal Differentiation After Vitamin A Acid," Arch. Klin. exp. Derm. 237: 744-795 (1970). No claim is made and no testing is disclosed in the Gander, et al. patents which indicates that the esters or amides show fewer or greater side effects than trans-retinoic acid.
The process for treating acne vulgaris topically utilizing retinal, the aldehyde form of vitamin A, is disclosed in U.S. Pat. No. 3,932,665. The aldehyde form, unlike the acid form of vitamin A, exerts its therapeutic effect without producing irritation, inflammation, erythema, or peeling of the skin. This patent also discloses the topical use of 13-cis-retinal in the treatment of acne vulgaris.
The method of treating acne with C-20 and C-22 vinylogs of desmethyl retinoic acid is disclosed in U.S. Pat. No. 3,882,244. These vinylogs as disclosed in the patent are applied topically to the site of the acne infection as a solution, ointment or powder. The treatment of acne vulgaris with retinoic acid analogs particularly 11-(2',6',6'-trimethylcyclohex-1'-enyl-1')-5,9-dimethylundeca-2,4,6,8,10-p entenoic acid is disclosed in U.S. Pat. No. 3,934,028. This compound can be used either internally or topically. When taken orally, the daily dosage of this compound ranged from 30-300 mg taken over from 2 to 8 weeks. However, there is no indication that the compound leads to remission from the disease after administration of the compound is withdrawn.
Although 13-cis-retinoic acid is generally less toxic than all-trans retinoic acid, there are still precautions that must be observed in its use. With oral retinoic acid, headaches, nausea, vomiting, and some of the skin and mucous membrane lesions experienced with hypervitaminosis A have been reported. Because of chemical and pharmacological similarities between 13-cis-retinoic acid, retinoic acid and retinol, similar adverse reactions occur with 13-cis-retinoic acid. See Blackman, et al., "Blepharoconjunctivitis: Side Effect of Oral 13-cis-Retinoic Acid Therapy of Dermatologic Disease," Ophthal. 85: 35, July 1978, and some of the above articles.
An improved method of treating nodulocystic and conglobate acne in human beings by oral administration of 13-cis-retinoic acid in amounts and for periods of time which afford an effectively complete remission from the condition even after administration of the compound ceases is disclosed in U.S. Pat. No. 4,322,438 to Peck.
The improvement over the prior art, was the use of a "high-low" oral dosage schedule, which proved effective in the treatment of cystic acne, while reducing the toxic effects of the 13-cis-retinoic acid. Further studies, (Jones, H., et al., "13-cis-Retinoic Acid and Acne," The Lancet, 1048, Nov. 15, 1980) however, have indicated that there are dose related side effects associated with the use of 13-cis-retinoic acid, particularly dryness of the skin and mucous membranes. More seriously, 13-cis-retinoic acid, which is marketed as an oral acne drug under the trademark Accutane.RTM. (isotretinoin/Roche), can cause serious birth defects. It also has a few other serious short-term side effects, such as increased pressure in the brain, clouding of the cornea and inflammation of the intestines. Physician's Desk Reference, at 1665-1667 (39th ed. 1985). Other drugs presently used in the treatment of acne include benzoyl peroxide, tretinoin (all-trans-retinoic acid, Retin-A-Ortho), clindamycin, tetracycline, erythromycin, minocycline, and estrogens (for females).
Benzoyl peroxide is considered safe and effective in mild and moderate acne treatment. Tretinoin is effective but has the previously mentioned deleterious side effects, as well as accelerating photocarcinogenesis. The antibiotics are reasonably effective but have side effects such as gastrointestinal problems including reports of pseudomembranous colitis. Estrogens are sometimes effective in treating acne, but the side effects of these drugs make them less than desirable.
Isotretinoin is the most dramatic and exciting breakthrough for the treatment of severe acne (Pochi, P. E., "Oral Retinoids in Dermatology," Arch. Dermatolo., 118: 57-61 (1982). The fact that it is irritating when applied topically (Popovich and Sperandio, "Current Topical Acne Therapy," Pharmacy Times, June, 104-115 (1984) and causes birth defects when administered orally (Robinson, "Isotretinoin," Drugs of Today, XVIII, 12: 642-649 (1982), however, prompted the present inventors to explore the possibility of inventing a prodrug of isotretinoin that would (1) be applied topically, (2) be absorbed by human skin, (3) be effective in the treatment of acne, and (4) be safe.
Also, since there is some indication that isotretinoin achieves remission in rosacea, gram-negative folliculitis, seborrhea, and keratinizing dermatoses (Bollag, "The Development of Retinoids in Experimental and Clinical Oncology and Dermatology," J. Amer. Acad. of Derm., 9: 797-805 (1983), it is reasonable to assume that the prodrugs of the present invention may be effective in the topical treatment of these skin disorders.
Finally, since the aromatic analog of retinoic acid, etretinate (Tigason-Roche) is effective in the oral treatment of severe psoriasis (Kaplan et al., "Etretinate Therapy for Psoriasis: Clinical Responses, Remission Times, Epidermal DNA and Polyamine Responses," J. American Acad. of Derm., 8: 95-102 (1983), topical retinoids might have an advantageous therapeutic index compared with drugs currently in use.
The present inventors are working under the hypothesis that topical administration of the drug of the present invention will result in less systemic toxicity compared with oral administration.
A topical prodrug that would retain the effectiveness of isotretinoin and would be essentially free of the deleterious side effects of isotretinoin would provide a much needed solution to a widespread problem.